Prion disease is a type of amyloidosis, like Alzheimer's disease and type 2 diabetes, but with the important distinction of being infectious. In these diseases abnormal folding of a cellular protein leads to its aggregation into fibrillar structures (amyloid), whose accumulation is associated with tissue degeneration. Amyloid formation appears to require a nucleation event, or seeding, but the precise nature of the seeds and what triggers their formation is unknown. What allows prions to be transmissible is also unknown. Our research, using yeast as a genetic system, is aimed at better understanding amyloid formation and replication, and in particular, what roles cellular factors play in prion propagation and transmissibility. We found that proper function of the essential protein chaperone Hsp70 is necessary for propagation of [PSI+], a prion form of yeast Sup35 protein. Hsp70 binds hydrophobic surfaces on partially folded proteins and prevents non-productive hydrophobic interactions that lead to aggregation. We isolated a mutant allele of HSP70 (SSA1-21) and showed that prions are extremely unstable in cells expressing Ssa1-21 protein. This instability was found to be due to a large reduction in the number of transmissible prion particles, or seeds, in SSA1-21 cells. More recently we found that in [PSI+] cells, the size of Sup35p aggregates is larger in SSA1-21 mutants, but there is also more soluble Sup35p. Our results suggest that Hsp70 acts in prion propagation by limiting aggregation, and that the SSA1-21 defect leads to formation of larger than normal aggregates that act poorly as prion seeds and are inefficient at recruiting the soluble form of the protein. Hsp104, a member of the Hsp100/Clp molecular chaperone family, is also important for yeast prion propagation. Hsp104's cellular role is to disaggregate stress-damaged proteins, and it may act in prion propagation by maintaining the aggregates in a form soluble enough to be efficiently transmitted. Yeast prion propagation is universally dependent on Hsp104 and is arrested by the presence of 5 millimolar guanidine HCl in growth media. We showed that this level of guanidine, routinely used to cure yeast prions, completely and specifically inhibits Hsp104 activity in vivo, providing an explanation for the twenty-year-old observation of its effect in curing yeast prions.